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<p>Mitochondrial dysfunction plays a crucial role in the pathophysiology of Type 1 Diabetes (T1D), as it compromises beta (β)-cell survival and insulin secretion. Autoimmune-driven inflammation disrupts mitochondrial homeostasis and thereby induces oxidative stress, disturbs calcium signaling, and activates apoptotic cascades that together impair β-cell viability. This review outlines mitochondrial quality control mechanisms, including fusion-fission dynamics, mitophagy, and cardiolipin remodeling, and explains how their dysregulation exacerbates β-cell dysfunction. In particular, mitochondrial proteins such as olfactomedin-4 modulate insulin release and thus provide potential therapeutic targets. Furthermore, crosstalk between the endoplasmic reticulum (ER) and mitochondria also influences β-cell resilience, with ER stress triggering pro-apoptotic signaling, particularly through CHOP-mediated pathways. Pharmacological approaches, including antioxidants, coenzyme Q10, dipeptidyl peptidase IV inhibitors, and imeglimin, together with natural agents such as SIRT3 activators and Vernicia fordii extracts, have shown efficacy in preserving mitochondrial integrity and promoting β-cell functions in animal studies. Further, this review also summarizes critical drug candidates, their mechanisms of action, and cellular outcomes. Collectively, emerging insights underscore mitophagy regulation, lipid metabolism, and calcium balance as promising avenues for restoring mitochondrial function and advancing therapeutic strategies in T1D.</p>

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Mitochondrial dysfunction in type 1 diabetes and its implications for pancreatic beta-cell survival and insulin secretion

  • 期刊论文

  • 发表日期：

    2025年11月10日

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  • Divya Ramesh Singh,
  • Shivam Malviya,
  • Sivaraj Mohana Sundaram

摘要

Mitochondrial dysfunction plays a crucial role in the pathophysiology of Type 1 Diabetes (T1D), as it compromises beta (β)-cell survival and insulin secretion. Autoimmune-driven inflammation disrupts mitochondrial homeostasis and thereby induces oxidative stress, disturbs calcium signaling, and activates apoptotic cascades that together impair β-cell viability. This review outlines mitochondrial quality control mechanisms, including fusion-fission dynamics, mitophagy, and cardiolipin remodeling, and explains how their dysregulation exacerbates β-cell dysfunction. In particular, mitochondrial proteins such as olfactomedin-4 modulate insulin release and thus provide potential therapeutic targets. Furthermore, crosstalk between the endoplasmic reticulum (ER) and mitochondria also influences β-cell resilience, with ER stress triggering pro-apoptotic signaling, particularly through CHOP-mediated pathways. Pharmacological approaches, including antioxidants, coenzyme Q10, dipeptidyl peptidase IV inhibitors, and imeglimin, together with natural agents such as SIRT3 activators and Vernicia fordii extracts, have shown efficacy in preserving mitochondrial integrity and promoting β-cell functions in animal studies. Further, this review also summarizes critical drug candidates, their mechanisms of action, and cellular outcomes. Collectively, emerging insights underscore mitophagy regulation, lipid metabolism, and calcium balance as promising avenues for restoring mitochondrial function and advancing therapeutic strategies in T1D.